Insulin Signaling

Targeting Receptor Stability

Science Signaling  05 Jul 2011:
Vol. 4, Issue 180, pp. ec186
DOI: 10.1126/scisignal.4180ec186

Before the onset of type 2 diabetes, individuals exhibit deficiencies in insulin signaling; identifying mechanisms by which such defects occur could provide new targets for therapies to treat the disease. Noting that microRNAs (miRNAs) are implicated in regulating metabolism, Trajkovski et al. performed miRNA microarray analyses of livers from two types of obese mice. The authors identified miR-103 and miR-107 as the miRNAs most increased in abundance in the livers of obese mice. Injection of wild-type mice with an adenovirus expressing miR-107 and green fluorescent protein (ad-107/GFP) resulted in increased serum glucose and insulin concentrations and increased hepatic production of glucose relative to that of mice treated with a control adenovirus. Conversely, silencing of miR-103 and miR-107 in liver and fat tissue in mice with a specific antagomir (ant-103) resulted in improved insulin sensitivity and glucose tolerance. Ant-103 resulted in a decrease in the size, but an increase in the number, of adipocytes in obese mice, and ant-103–treated adipocytes showed increased differentiation in vitro relative to that of adipocytes treated with a control antagomir. Caveolin-1 was identified as a target of miR-103 and miR-107, and ant-103–treated obese mice exhibited increased amounts of caveolin-1 and the insulin receptor β-subunit in liver and adipose, effects that were associated with increased insulin signaling. Treatment of caveolin-1–deficient mice with either ad-107/GFP or ant-103 had no effects on glucose tolerance or insulin sensitivity. Together, these data suggest that inhibiting the function of miR-103 and miR-107 leads to increased insulin sensitivity by increasing caveolin-1 abundance and insulin receptor stability, thus providing potential therapeutic targets for the treatment of diabetes.

M. Trajkovski, J. Hausser, J. Soutschek, B. Bhat, A. Akin, M. Zavolan, M. H. Heim, M. Stoffel, MicroRNAs 103 and 107 regulate insulin sensitivity. Nature 474, 649–653 (2011). [PubMed]